Project Summary: Nicotinic acetylcholine receptors underlie widespread modulatory processes throughout the brain including the auditory pathway. Acetylcholine release is driven both by behavioral state and in response to specific stimuli. For example, activation of nicotinic receptors is a key mechanism of prepulse inhibition, a physiological manifestation of sensory gating in the auditory system. These processes are deficient in schizophrenic patients, a patient population with a high tendency to self-medicate with nicotine. Therapeutic interventions that reverse auditory processing deficiencies in these patients directly or indirectly target nicotinic receptors. Previous investigation of cholinergic modulation in the auditory system has focused on the auditory cortex, but also to a lesser extent in the cochlear nucleus. However, the same cholinergic pathways that project to the cortex also provide input to lower auditory centers in the brainstem. The superior olivary complex is a major component of the auditory pathway and includes the medial nucleus of the trapezoid body (MNTB) and its postsynaptic target the medial superior olive (MSO). Both nuclei process sounds with extreme temporal precision, a computational process essential to detection of signals in noise, speech sounds and sound localization. Indeed, the MSO is the first sight of binaural integration in the auditory pathway, and performs the fundamental sound localization computations. MNTB and MSO express markers suggesting a prominent role for cholinergic modulation of these processes. However, cholinergic inputs have never been investigated in these regions, leaving a critical gap in our understanding of SOC function. The central hypothesis of this proposal is that cholinergic input exerts an acoustically driven modulation of the excitatory afferent terminals in the SOC and their postsynaptic targets in the MNTB and MSO. The primary objective of this research proposal is to build a mechanistic understanding of cholinergic modulation in MNTB and MSO, and to reveal its role in shaping responses to acoustic input. This objective will be achieved by pursuing three Specific Aims: 1) Determine the mechanisms of cholinergic modulation of presynaptic inputs to MSO and MNTB neurons; 2) Investigate the functional consequence of AChR expression by principal neurons in MNTB and MSO; 3) Reveal the specific computational contribution of acoustically driven cholinergic modulation of MNTB and MSO neurons. These aims constitute a novel and innovative approach to understanding fundamental computations in the temporal processing pathway. The data derived from these studies will provide substantial insight into a very poorly understood but potentially important neural feedback system in the auditory pathway. The specific investigation of temporal processing neurons will reveal mechanisms that may enhance our understanding of how such temporal precision is achieved in the sound localization pathway.